In preparing pharmaceutical and biological materials for parenteral use, the material must be sterile and often must be concentrated. One method of concentrating these materials is by centrifugation. For viscous gels, centrifugation has associated problems of product recovery, aseptic operation and the maintenance of a closed system. Another method includes filtration. In conventional dead-end filtration with a stationary filter medium or membrane the liquid mixture flows perpendicular to the filter media. In tangential flow filtration, the liquid mixture passes tangentially past the filter media and the filtrate (permeate) passes through the medium. In such filtration, separation only occurs at the liquid-media boundary (i.e., the boundary layer). The boundary layer tends to retain the filtered particles which are prevented from returning to the bulk solution. This leads to concentration polarization and in some cases to formation of gel layers on the filter media. Clogging or blinding of the filter media is a problem at any level of filtration, insofar as transmembrane flow (i.e., flux) drops as the pores in the filter media become clogged. To eliminate clogging and blinding, vortex flow filtration has been known to be used.
Vortex flow filtration devices typically employ a semi-permeable membrane as the filtration media. The vortex flow filtration apparatus relies on certain components of the filtered material being much more permeable through the membrane than other components. The purpose of the vortex flow filtration apparatus is to separate one or more substances by retaining some on one side of a membrane as a "retentate" while passing others through the membrane as a "permeate". In the processing of pharmaceutical and biological materials, often the concentrated retentate is the valuable portion and the permeate is drained off.
Vortex flow filtration uses a known hydrodynamic phenomenon to prevent clogging or blinding of the filter media caused by the accumulation of dissolved or suspended material thereon. The operation of these systems is discussed in U.S. Pat. Nos. 4,790,942, 4,876,013, and 4,911,847 issued to Shmidt et al., which are incorporated herein by reference in their entirety.
In short, the vortex flow filtration device discussed in these references uses a membrane mounted on an inner body which rotates within a stationary outer body. The vortex flow apparatus prevents clogging by producing Taylor vortices in the parent fluid in the annular gap between the inner body and the stationary outer body. However, there is a need for a device that can effectively concentrate gels and/or semisolids, such as aqueous collagen dispersions, for parenteral use.
The known vortex flow filtration devices of the prior art are equipped with graphite bearings which are adequate for their intended purpose of separating cell culture or fermentation cells from the liquid content. These systems may be sterile but produce small levels of graphite particulates shed from the bearings, which is tolerable for separation purposes if the product produced is not intended for parenteral use.
Purified bovine collagen is used in a variety of medical devices including hemostats, sutures, corneal shields, and soft tissue augmentation. Collagen gels are often intermediates in the preparation of these devices and, in some cases, the gels represent the final medical products.
Sterile bovine collagen dispersions and gels with concentrations up to 10 % (w/w) and higher are commercially available. These formulations are prepared by conventional processes whereby collagen is precipitated from solution and aseptically concentrated. A concentration/separation technique commonly employed is centrifugation. Centrifugation may require high capital expenditure; and presents sterilization and validation challenges and has product recovery problems for viscous, adhesive materials. Other separation techniques have also been found to be unsatisfactory. For example, conventional dead end filtration and tangential flow filtration are not feasible because collagen fibers tend to clog or blind the filters.
Technical problems associated with concentrating collagen gels are attributable, in part, to their high viscosity and cohesive and adhesive properties. For example, aqueous collagen products having about 0.3% (wt) to about 11% (wt) solids have viscosities ranging from about 30 mPa.multidot.sec to about 40,000 mPa.multidot.sec.
There is a need to provide an effective means for aseptically concentrating pharmaceutical and biological materials, including collagen and other gels and semisolids. The present invention offers such an apparatus for aseptic filtration/concentration of pharmaceutical and biological materials (particularly semisolids and/or gels), such as aqueous dispersions of collagen.